PCD Protocol

PCD Protocol#

Writer : HeeSeok Yoo#

Pre-Extubation Dexmedetomidine Switch Strategy(PEDSS) — A Master Protocol with Thoracic Surgery, ARDS, and Sepsis#

Administrative Information#

  • Title: Pre-Extubation Dexmedetomidine Switch Strategy(PEDSS) — A Master Protocol with Thoracic Surgery, ARDS, and Sepsis

  • Trial registration: (ClinicalTrials.gov)[ClinicalTrials.gov]

  • Protocol version: Ver 1.0

Introduction#

Background and Rationale#

  • Sedation strategies prior to extubation impact delirium incidence, reintubation rates, and recovery speed.

  • Propofol plus opioid (e.g., remifentanil) is common in ICUs but is associated with risks of respiratory depression, increased delirium risk, and delayed recovery.

  • Dexmedetomidine (Precedex) produces cooperative/light sedation with minimal respiratory depression, and may reduce delirium risk when substituted for propofol prior to extubation.

  • This platform–basket design aims to evaluate this switch strategy across distinct patient populations (thoracic surgery, ARDS, sepsis) and test a common primary hypothesis while exploring heterogeneity of treatment effect.

Evidence base (including propofol long-term safety)#

  • Propofol is widely used due to its rapid onset, short duration, and titratability.

  • However, prolonged high-dose use (days to weeks) carries risk of Propofol Infusion Syndrome (PIS), which can cause heart failure, metabolic acidosis, hyperkalemia, rhabdomyolysis, renal failure, and hepatic dysfunction.

  • Other rare adverse effects include hypertriglyceridemia, pancreatitis, and metabolic derangements.

  • Short-term use (24–72 h) at standard doses is associated with very low rates of severe adverse effects, and is considered safe in current international ICU sedation guidelines.

  • In this trial, the control arm will generally involve ≤48 h of propofol at standard doses; PIS and other serious adverse events are expected to be extremely rare, but safety monitoring will include hemodynamic parameters, metabolic markers, and CK.

Hypothesis#

  • The Precedex switch arm will have a lower incidence of delirium within 72 h after extubation compared to the standard arm.

Objectives#

  • Primary objective: To compare the incidence of delirium (CAM-ICU) within 72h post-extubation between groups.

  • Secondary objectives: To compare reintubation rates, ICU length of stay (LOS), ventilator-free days at day 28 (VFD-28), pain/sedation target achievement, cumulative opioid use, safety, and laboratory changes.

Trial Design#

  • Multicenter, three-basket (thoracic surgery / ARDS / sepsis) platform

  • Two-arm randomized controlled trial, open-label treatment, blinded outcome assessment

  • Stratified randomization by basket, site, age, and sex

  • Primary analysis at platform level; exploratory basket-specific analyses with FDR adjustment

Participants#

Inclusion criteria#

  • Age ≥60 years, invasive mechanical ventilation, ≥24h of propofol + remifentanil sedation

  • Planned extubation within 24h

  • Sedation target RASS -2 to 0

Exclusion criteria#

  • HR <40 bpm, high-grade AV block, uncorrectable MAP <55 mmHg

  • Severe hepatic impairment

  • Inability to assess CAM-ICU, terminal care plan in place

  • Deemed unsuitable by investigator

Interventions#

Arm A (Standard Care)#

  • Propofol at institutional standard rate + remifentanil

  • Continued until extubation

Arm B (Switch Strategy)#

  • 6–12h before planned extubation, stop propofol and initiate dexmedetomidine (0.2–0.7 µg/kg/h, no loading dose)

  • Adjust to RASS -2 to 0

  • Maintain remifentanil at minimal effective dose

Common to both arms#

  • Rescue benzodiazepine use minimized

  • Stepwise dose reduction and stopping rules for hypotension/bradycardia

  • Analgesia-first approach

Outcomes#

Primary endpoint:#

  • Delirium within 72h post-extubation (≥1 positive CAM-ICU assessment)

Secondary endpoints:#

  • Reintubation rate (24h, 48h), ICU LOS, VFD-28

  • Sedation target achievement (RASS), SAT/SBT performance

  • Cumulative opioid dose (morphine equivalents)

  • Safety (AEs, SAEs), lab changes (CRP, cortisol, LFTs, BUN/Cr)

Sample Size#

  • Control delirium rate 35%, intervention 25% (absolute reduction 10%); α=0.05, 1–β=0.80 → 325 per arm

  • Allowing 10% dropout: 360 per arm, total 720 participants

Data Management and Statistical Analysis#

  • eCRF compliant with 21 CFR Part 11

  • Primary analysis: logistic regression (group, basket, site; covariates: age, sex, severity)

  • Time-to-event: Kaplan–Meier / Cox regression

  • Missing data: multiple imputation

  • Interaction analyses: Bonferroni / FDR adjustment

Safety#

  • DSMB oversight, stopping rules in place

  • Standard safety monitoring including CK, lipids, acid–base status (for early PIS detection)

  • Suspected PIS: immediate protocol discontinuation, treatment change

Ethics#

  • IRB approval at all sites prior to initiation

  • Deferred consent permitted per institutional SOP

  • Data confidentiality maintained via de-identification and encryption

  • Compensation for study drug-related injury as per institutional policy

Appendices#

  • Participant flow diagram

  • Assessment schedule (Gantt chart)

  • Drug titration and reduction algorithm

Contents